American Chemical Society
es204506g_si_001.pdf (1.63 MB)

Compound Lipophilicity as a Descriptor to Predict Binding Affinity (1/Km) in Mammals

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journal contribution
posted on 2012-05-01, 00:00 authored by Alessandra Pirovano, Mark A. J. Huijbregts, Ad M. J. Ragas, A. Jan Hendriks
In bioaccumulation models, biotransformation is one of the processes decreasing the concentration of chemicals in an organism. In order to be metabolized, a compound needs to bind to an enzyme. In this study, we derived relationships between binding affinity and lipophilicity, expressed as Log (1/Km) and Log Kow, respectively. We focused on oxidations in mammals catalyzed by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), flavin-containing monooxygenase (FMO), and cytochrome P450 (CYP) enzymes. For all regressions, 1/Km increased with compound Kow, which can be understood from the tendency to biotransform lipophilic compounds into more polar, thus more easily excretable metabolites. Lipophilicity was relevant to the binding of most of the substrate classes of ADH, ALDH, and CYP. The resulting slopes had 95% Confidence Intervals covering the value of 0.63, typically noted in protein-water distribution (Log Kpw) and Log Kow regressions. A reduced slope (0.2–0.3) was found for FMO: this may be due to a different reaction mechanism involving a nucleophilic attack. The general patterns of metabolism were mechanistically interpreted in terms of partitioning theory. Information on the overall principles determining biotransformation may be helpful in predicting metabolic rates.